Molecular dynamics of xenon in cryptophane-A

Abstract

The classical nuclear magnetic resonance (NMR) relies on abundant sources of hydrogen nuclei, usually in water and fat of biological tissue. This renders the detection of biochemical phenomena at very low concentrations not feasible. If the details of the microsopic phenomena were understood, a description of, e.g., diseases at a molecular level, could be given. This calls for development of new microscopic machines that are capable of molecular recognition in a desired environment.

Xenon NMR biosensors have risen as promising candidates of novel molecular probes. They combine the known advantages of NMR with the chemical shift sensitivity of xenon that functions as a guest atom in a functionalised host molecule. The principle of the method is the following: When the biosensor binds to a target molecule, e.g., a specific protein produced by cancer cells, via the so-called targeting units of the host molecule, the chemical structure of the host changes. Through a network of interactions, this change is carried out to the electron cloud of xenon. Due to extreme sensitivity of the electron cloud, even the smallest chemical changes of the host structure can be seen in the NMR spectrum of the xenon nucleus.

Cryptophanes are a well-documented and a popular category of host molecules for the biosensor application. They are spherical in shape and have a hydrophobic cavity, capable of atomic and molecular encapsulation via non-covalent van der Waals interactions. Cryptophanes meet with majority of the requirements of potential host molecules for xenon biosensors. Detailed microscopic description of the non-covalent interactions of xenon cryptophane complexes is experimentally very difficult, so computational modeling is required.

In this thesis, the host-guest interactions between xenon and cryptophane-A are studied. Cryptophane-A is a simple and a commonly used variant of the cryptophane molecules. In the present work, no targeting units are attached on the host structure, so the studied system is a prototype of a complete xenon biosensor. In particular, xenon binding free energy and complexation mechanism with the host molecule, as well as the role of water molecules as explicit solvent are investigated.

Molecular dynamics (MD) and metadynamics (MTD) simulations were performed at semiempirical and force-field levels of theory to study the potential xenon biosensor in its natural solvent environment. The MD outputs were used to calculate the binding free energy of xenon through a thermodynamic cycle, and also to compute the exchange dynamics of water molecules with the cryptophane host. The dissociation of xenon from the cryptophane-A, which is an extremely rare event at the molecular time scale, could be reproduced by the MTD simulations.

The simulations provided insight into the xenon biosensor host-guest interactions at a molecular level. The binding free energy results are in good agreement with existing experimental and computational values. For the first time, the complexation mechanism and route of xenon from the cryptophane host was identified. In the present simulations, xenon was found to dissociate in three qualitatively different processes, each initialised by the inclusion of water molecules. The obtained exchange dynamics and mean residence times of water molecules are in agreement with previous computational results.